Both lower 25-hydroxyvitamin D (25[OH]D) and higher uric acid levels are associated with activation of the renin angiotensin system, endothelial dysfunction, and elevation of blood pressure in humans. Furthermore, lower 25(OH)D and higher uric acid levels are associated with overweight and obesity, and may be potential mediators of the adverse effects of adiposity on renin angiotensin system activation, endothelial dysfunction, and blood pressure. However, the effects of vitamin D supplementation and uric acid lowering on these underlying mechanisms of hypertension, cardiovascular and chronic kidney disease are unknown. The MODERATE (MODififable Effectors of Renin system Activation: Treatment Evaluation) study is a randomized, double blind, placebo controlled, clinical trial comparing 50,000 units/week of vitamin D supplementation to placebo for 8 weeks, or comparing uric acid lowering with either allopurinol 300 mg/day or probenecid 500 mg/day (both with a dose titration at 4 weeks to 600 mg/day or 1000 mg/day, respectively) to placebo for 8 weeks. Overweight or obese adults with vitamin D deficiency or uric acid levels e 5 mg/dL will be enrolled, and the primary endpoint will be the activation state of the renin angiotensin system, as determined by the plasma renin activity, angiotensin II concentration, and the renal plasma flow response to infused angiotensin II with individuals in high-sodium balance. The secondary endpoint will be endothelial dependent dilation measured by reactive hyperemia with high resolution ultrasound, and the tertiary endpoint will mean 24 hour systolic and diastolic blood pressure measured with an ambulatory blood pressure device. From a scientific standpoint, this trial will provide the first experimental human data regarding the effects of 25(OH)D and uric acid on renin angiotensin system activation and endothelial function, which are two critical mechanisms of disease. From a public health standpoint, the results of this trial will inform strategies and future trials designed to prevent the incidence of hypertension, cardiovascular and chronic kidney disease. PUBLIC HEALTH RELEVANCE: People with vitamin D deficiency and higher blood levels of a compound called uric acid may be at risk for developing high blood pressure, heart attacks, and kidney disease because their bodies produce inappropriate amounts of certain hormones and because their blood vessels do not function normally. People who are overweight or obese are more likely to have vitamin D deficiency and high levels of uric acid. This study will determine whether giving vitamin D supplements or medication to lower uric acid levels to overweight or obese people can reverse some of the hormone and blood vessel abnormalities that ultimately could cause high blood pressure, heart attacks, and kidney disease.